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The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central
regulator in the development of several cancer types. In recent years, intriguing information has
become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM),
the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes
in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell
behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5)
and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple
intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular
actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs
and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P
involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq,
and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be
elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its
receptors in GBM. We further highlight the current insights into the signaling pathways considered
fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.
Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been
shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell
migration by transforming growth factor (TGF)-β1. However, it is not known whether activation
of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular signal-regulated kinase (ERK)
signaling) is required for cell migration and whether it is also dependent on PAR2. Methods: RNA
interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure
cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation
to detect a PAR2–ALK5 physical interaction. Results: Inhibition of ERK signaling with the MEK
inhibitor U0126 blunted the ability of TGF-β1 to induce migration in pancreatic cancer Panc1 cells.
ERK activation in response to PAR2 agonistic peptide (PAR2–AP) was strong and rapid, while it was
moderate and delayed in response to TGF-β1. Basal and TGF-β1-dependent ERK, but not SMAD
activation, was blocked by U0126 in Panc1 and other cell types indicating that ERK activation is
downstream or independent of SMAD signaling. Moreover, cellular depletion of PAR2 in HaCaT
cells strongly inhibited TGF-β1-induced ERK activation, while the biased PAR2 agonist GB88 at 10
and 100 µM potentiated TGF-β1-dependent ERK activation and cell migration. Finally, we provide
evidence for a physical interaction between PAR2 and ALK5. Our data show that both PAR2–APand TGF-β1-induced cell migration depend on ERK activation, that PAR2 expression is crucial for
TGF-β1-induced ERK activation, and that the functional cooperation of PAR2 and TGF-β1 involves a
physical interaction between PAR2 and ALK5
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated
in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer,
it usually acts as a driver of cancer progression in various tumor types by promoting invasion and
metastasis in response to activation by serine proteinases. Recently, we discovered another mode
through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β
(TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene
expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is
known about the cellular TGF-β responses and signaling pathways affected by PAR2 expression,
the signaling activities of PAR2 required for promoting TGF-β signaling, and the potential molecular
mechanism(s) that underlie(s) the TGF-β signaling–promoting effect. Since PAR2 is activated through
various serine proteinases and biased agonists, it may couple TGF-β signaling to a diverse range of
other physiological processes that may or may not predispose cells to cancer development such as
local inflammation, systemic coagulation and pathogen infection.